Cholesterol, a component of all eukaryotic plasma membranes, is essential for the growth and viability of cells in higher organisms. However, high serum levels of cholesterol cause disease and death by contributing to the formation of atherosclerotic plaques in arteries throughout the body. The major site of cholesterol synthesis in mammals is the liver. Appreciable amounts of cholesterol are also formed by the intestine. The rate of cholesterol formation by these organs is highly responsive to the amount of cholesterol absorbed from dietary sources. Cells outside of the liver and intestine acquire cholesterol from the plasma rather than by synthesising it de novo. Cholesterol and other lipids are transported in body fluids by lipoproteins, which are classified according to increasing density. A lipoprotein is a particle consisting of a core of hydrophobic lipids surrounded by a shell of polar lipids and apoproteins. These lipoproteins have two roles: they solubilize highly hydrophobic lipids and they contain signals that regulate the movement of particular lipids in and out of specific target cells and tissues. Cholesterol is transported in body fluids by low-density lipoproteins (LDL) which binds to a specific receptor on the plasma membrane of non hepatic cells. The receptor-LDL complex is then internalised into the cells by a transport mechanism known as receptor mediated endocytosis (Goldstein et al. 1979). The low density lipoprotein (LDL) receptor is the prototype of a family of structurally related cell surface receptors that mediate endocytosis of multiple ligands in mammalian cells.
The nucleotide sequence of a cloned 5.3 kilobase cDNA for the human LDL receptor revealed five structural domains, some of which share sequence homology with other proteins. Its NH2-terminal ligand-binding domain consists of 322 residues, which include 47 cysteine residues. This domain is followed by four additional domains: the first consists of about 350 amino acid residues and is homologous to the EGF receptor, the second consists of 48 amino acid residues rich in O-linked sugars, the third is a single trans-membrane domain of 22 amino acid residues and the fourth is a cytoplasmic domain of 50 amino acid residues (Yamamoto et al 1984).
A soluble form of the LDLR exhibiting antiviral activity, sLDLR, was identified and isolated from the culture supernatant of interferon-induced cells (Fischer et al. 1993) and in body fluids (Fischer et al. 1994). Several interferon-induced proteins have been identified that are instrumental in the induction of the antiviral state by IFNs. One such protein exhibiting antiviral activity was produced and accumulated in the culture supernatant of human amnion WISH cells. This protein was purified to homogeneity and identified as the sLDLR (see EP 0 553 667 and Fischer et al. 1993). The sLDLR was found to be secreted into the medium by mammalian cells that enter an antiviral state in response to interferon. In contrast to interferon, sLDLR does not induce an antiviral state in the cells but is antiviral by itself. It was found that sLDLR apparently has to be present throughout the process of viral replication maturation and budding suggesting it might be involved in a complex process that leads to the inhibition of virus assembly or budding (unpublished data). Endocytosis of the hepatitis C virus has been recently shown to be mediated by LDL receptors on cultured cells (Agnello et al. 1999).
Liver damage or injury may have diverse causes. It may be due to viral or bacterial infections, alcohol abuse, immunological disorders, or cancer, for example.
Viral hepatitis, due to Hepatitis B virus and Hepatitis C virus are poorly managed diseases that afflict large number of people world-wide. The number of known hepatitis viruses known is constantly increasing. Apart from Hepatitis B and C virus, at least four other viruses causing virus-associated hepatitis have been discovered so far, called Hepatitis A, D, E and G-Virus.
Lamivudine (3TC), trade name Epivir, an anti HIV treatment, is also approved for the treatment of hepatitis B. Studies have shown that Epivir can reduce the amount of hepatitis B virus to very low levels, although this effect does not always last.
Adefovir Dipovoxil (ADV) is another HIV treatment that has been shown to be effective in chronic hepatitis B.